Nutritional supplements and pharmaceutical agents are typically provided in solid dosage formulations that are taken orally. Examples of solid dosage forms include coated tablets, compressed tablets, compressed capsules and two piece gelatin capsules. Such forms have the advantage of being easy and relatively inexpensive to produce, readily dispensable, and fairly stable. Dosage form is an important factor that influences the absorption and bioavailability of a compound.
Solid dosage formulations of drugs and nutritional supplements have the disadvantage that many of the ingredients in the supplement are degraded by stomach acids. Degradation within the stomach serves to decrease the therapeutic response to orally administered solid agents. Degradation can be an important factor which limits the effectiveness of drugs and nutritional supplements, such as plant extracts, which are taken for medicinal purposes.
Another disadvantage to solid dosage forms is that a fraction of the population is either unable to swallow the solid form or are reluctant to take such "pills." Further, the gag reflex action provides a barrier to tablet size. As the size of the solid form increases, the percentage of people who will have trouble swallowing the solid form also increases. This problem becomes particularly acute when high dosages are required to overcome degradation such as with the administration of many pharmaceutical agents and nutritional supplements taken for medical or other purposes.
The activity of a substance that is administered into the mouth is largely dependent on the amount of the substance that reaches the bloodstream and the rate at which it reaches the bloodstream. By increasing the rate and extent of absorption, the activity of the substance can be enhanced, therefore reducing the amount needed in the oral formulation. It has become increasingly important in the area of substance delivery, and in the treatment of any disease or disorder, to increase the availability of the substance. However, in general, this focus has not been applied to nutritional supplements.
The term availability is used to indicate the completeness of absorption. The term bioavailability is a term for the clinical description of availability in vivo and indicates the extent to which a substance reaches the bloodstream. Bioavailability is defined as the fraction or percentage of the administered dose that is ultimately absorbed intact. (Rowland and Tozer, "Clinical Pharmacokinetics: Concepts and Applications," (1980), pp. 16-31.
The rate or speed of absorption and the extent or ratio of the amount of active material absorbed over the amount administered depends on several factors. The most important factors include, 1) dosage form and delivery system, 2) physicochemical properties of the drug, particularly solubility, 3) dose, 4) site of administration, 5) vascularization of the absorption site, 6) contact time with the absorption surface, and 7) pH at the site of absorption. (Mutschler and Derendorf, "Drug Actions: Basic principles And Therapeutic Aspect", (English Ed 1995), pp. 11-26.
Solid dosage forms are absorbed following oral administration by a two-step process. This two-step process can be the rate limiting step in the absorption process that can delay onset of action and slow the therapeutic response by the patient. The two-step process is 1) dissolution of the solid dosage and 2) absorption of drug in solution.
Many compounds that are orally administered are chemically defined as weak acids or weak bases and exist in solution as an equilibrium between the nonionized and the ionized forms. Increased accumulation of compound on the side of membrane whose pH favors a greater ionization of the compound has led to the pH partition hypothesis. According to this hypothesis, only a nonionized nonpolar drug penetrates the membrane, and at equilibrium the concentration of the nonionized species is equal on both sides of the membrane. The nonionized form is assumed to be sufficiently lipophilic to penetrate the membrane. If it is not, there is no absorption, irrespective of pH. The fraction of nonionized compound at the absorption site is controlled by both the pH and pKa of the compound, according to the Henderson-Hasselbalch equation. (Goodman and Gilman's "The Pharmacological Basis of Therapeutics", 9th ed. (1996) pp. 4-22).
The mucosa of the mouth and throat is highly vascularized and well suited for the absorption of lipophilic, nonionized compounds. These routes of absorption are particularly advantageous for compounds that are needed to have a rapid onset of action or are not well absorbed when taken orally. This route of administration circumvents exposure of compounds to digestive enzymes and the high acidity of the gastrointestinal tract that can be damaging to compounds and render them inactive.
Administration by the sublingual or buccal route further avoids the first-pass effect from hepatic enzymes immediately upon absorption. The term first-pass effect is used to characterize the fraction of the drug that is metabolized during the first exposure to the gut wall and the liver. All compounds that are absorbed from the gastrointestinal tract go to the portal vein and the liver before entering the systemic circulation. This means that before a drug that has been absorbed across the membrane of the gastrointestinal mucosa can reach the general circulation it has to pass through the liver.
There are some biologically active compounds that are delivered sublingually to achieve a rapid onset and greater bioavailability. For example, by administering nitroglycerin tablets under the tongue, rapid onset is achieved by virtue of quick absorption into the blood stream through the highly vascularized capillary plexus. In addition this route avoids the liver where the compound is highly metabolized on first exposure to metabolic enzyme systems. Another example of a compound that is administered orally for absorption in the mouth is methyltestosterone. Supplied in tablet form that is designed for absorption through the buccal mucosa into systemic circulation, this route provides twice the androgenic activity of oral tablets. Another approach to the administration of compositions such as vitamins is disclosed in U.S. Pat. No. 4,525,341 to Deihl which involves the production of an aerosol administered with a pulmonifer in the form of a suspension of droplets dispersed in a carrier gas. However, none of the available compositions for oral absorption have been formulated in the form of lipid encapsulation.
A variety of liposomal products are known that enhance uptake or facilitate delivery of various products. For example, the parenteral and topical uses of liposomal carriers were reported to protect a drug against hostile environments and to provide controlled release of the drug while circulating in the blood or after immobilization at a target tissue such as the skin. "Liposome Technology", 2nd Ed, Vol. I (1993) G. Gregoriadis ed., CRC Press, Boca Raton, Fla. The topical administration of drugs such as Minoxidil.RTM. has been reported by Mezei (U.S. Pat. No. 4,897,269) as well as the pulmonary administration of liposomes-encapsulated opioid analgesic agents (U.S. Pat. No. 5,451,408). Mezei also has reported the use of a topical liposomal local anesthetic product said to be useful in producing local anesthesia of mucous membrane-covered surfaces (U.S. Pat. No. 4,937,078).
Despite the foregoing advantages of sublingual routes of administration and of the use of lipid encapsulation, these two methods have not been combined and applied to drug and nutritional supplement delivery, particularly in an aerosol or spray delivery form. The present invention provides novel delivery systems for administering agents, such as drugs and nutritional supplements, whereby the agent is lipid encapsulated, into lipid vesicles or liposomes, and administered as an aerosol or spray into the mouth for subsequent absorption in the mouth, the throat and/or the gastrointestinal tract. The results provided in the Examples indicate that such lipid encapsulated aerosol or spray formulations provide increases in the bioavailability and improved therapeutic response for a wide variety of pharmacological agents and nutritional supplements.